Combination of genetics at baseline and clearance of MRD to assign the post-remission treatment of patients with Philadelphia-negative ACUTE lymphoblastic leukemia. FINAL results of pethema LAL19 trial

Abstract Introduction. Adults with Ph-negative acute lymphoblastic leukemia (Ph- ALL) may not require allogeneic hematopoietic stem cell transplantation (alloHSCT) if they achieve negative measurable residual disease (MRD) after induction and consolidation therapy. However, it is unclear whether baseline genetic risk could more accurately identify patients (pts) who should receive chemotherapy (CHT) or alloHSCT. The aim of the PETHEMA LAL19 protocol (NCT04179929) was to evaluate the outcomes of pts assigned to differentiated post-induction therapy (CHT or alloHSCT) according to genetic features at diagnosis and MRD levels after induction. Methods. PETHEMA LAL19 was a multicenter study, including data from 94 centers across Spain. It enrolled newly diagnosed Ph-negative ALL pts, both T- and B-lineage, who received a pediatric-inspired treatment. Pts with high-risk (HR) genetics, those requiring two induction cycles to achieve complete remission (CR), and those with CR but MRD ≥0.01% after induction-1 (Ind-1) or MRD ≥0.001% after early consolidation and reinduction were allocated to alloHSCT. The remaining pts, considered standard-risk pts, were assigned to late consolidation and maintenance. HR genetics in B-ALL included: KMT2A rearrangement, hypodiploidy (<40 chromosomes) in pts aged >35 years, homozygous TP53 mutations/deletions, or co-occurrence of IKZF1 and CDKN2A deletions. HR genetics in T-ALL included absence of NOTCH1/FBXW7 mutations and/or mutations in K/NRAS or PTEN. Early T-cell precursor (ETP) ALL pts received a different treatment and all of them were assigned to receive an alloHSCT in first CR. All MRD and genetic studies were centralized. Results. Between end 2019 and August 2024, 436 eligible pts were enrolled (413 non-ETP and 23 ETP). In the non-ETP group, median age was 40 years (range, 18–60), 56% were male, median WBC count was 12×10⁹/L (0.4–740), and 80% had B-ALL. HR genetics were found in 36% (99/274) of B-ALL pts and 52% (34/65) of T-ALL cases. CR rate after Ind-1 was 84% (348/413) and increased to 95% (387/407) after Ind-1+Ind-2. MRD <0.01% was achieved in 63% (221/348) post-Ind-1 and in 91% (324/357) post-Ind-1+Ind-2. In the ETP-ALL group (n=23), median age was 29 years (range, 18-57), 57% were male, median WBC count was 29.2×10⁹/L (3.5-389), and five patients had CNS involvement. The CR rate was 74% (17/23) with 7 (41%) pts being MRD <0.01% after Ind-1 with FLAG-IDA. By intention-to-treat, 243 pts (61%) from the non-ETP group were allocated to alloHSCT and 157 (39%) to CT. The 3-year overall survival (OS) was 64% (95% CI, 58%–69%), and the cumulative incidence of relapse (CIR) was 39% (33%–45%). Among pts with CR and MRD <0.01% after Ind-1 and without HR genetics (n=109), 3-year OS was 81% (70%–89%). This compares favorably with 50% (34%–63%) observed in genetically HR pts (n=64) with similar MRD clearance, as well as with 58% for pts with CR and MRD ≥0.01% and 53% for pts who did not achieve CR after Ind-1 (p<0.001). A very-good risk group of patients (absence of HR genetics & CR after ind-1 with MRD<0.01% & MRD<0.001% after Re-Induction) showed a 3-year OS of 89% (78%–95%) and a 3-year CIR of 19% (10%-31%) with CHT only. In ETP-ALL pts, the 3-year OS was 61% (37%–79%), and the CIR was 25% (8%–48%). Conclusions. In adults with Ph- ALL, assigning post-remission treatment based on MRD and genetic risk is feasible. Genetic risk assessment among pts with good MRD clearance identified a subgroup with excellent prognosis without the need for alloHSCT. Thus, integrating genetic risk with MRD improves the precision of risk stratification.

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Journal
Blood
Published
2025-11-03
DOI
https://doi.org/10.1182/blood-2025-5121
Primary Topic
Acute Lymphoblastic Leukemia research
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article
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article

Combination of genetics at baseline and clearance of MRD to assign the post-remission treatment of patients with Philadelphia-negative ACUTE lymphoblastic leukemia. FINAL results of pethema LAL19 trial

Mónica Cabrero Calvo, Pilar Martínez‐Sánchez, Pau Montesinos, Mar Tormo et al.
Blood
Acute Lymphoblastic Leukemia research
article

Combination of genetics at baseline and clearance of MRD to assign the post-remission treatment of patients with Philadelphia-negative ACUTE lymphoblastic leukemia. FINAL results of pethema LAL19 trial

Mónica Cabrero Calvo, Pilar Martínez‐Sánchez, Pau Montesinos, Mar Tormo, Susana Barrera, Bernardo González, Ferran Vall‐Llovera Calmet, Jose Ángel Raposo Puglia, Alberto Hernández‐Sánchez, Maria Queipo De Llano, Mará Sol Casado Calderón, Mireia Morgades, María José García Sánchez, Lorenzo Algarra, Irene García‐Cadenas, Jesús María Hernández‐Rivas, Edgar Zapico, Eulàlia Genescà, María Lourdes Amador Barciela, Pere Barba, Isabel Granada, Laura Solán, Clara Maluquer Artigal, Antonia Cladera Serra, Josefina Serrano, Ricardo Sánchez, Angelo Castello, Ignacio Gómez‐Centurión, Esperanza Such, Juan Bergua, Juana Ciudad, Verónica Roldán Galiacho, Núria Martínez‐Cibrián, Paula Lopez de Ugarriza, José González‐Campos, Carmen Botella, Josep‐María Ribera, Anna Torrent, Alberto Órfão, María Solé Rodriguez, Laura Llorente González, M.S. Lorenzo, Jordi Ribera, Lucía Gómez Pérez, Arancha Bermúdez, Raimundo García, Carlos Rodriguez Medina, Marta Sitges Arriaga, María Hermosín-Ramos, Daniel Barrios Decoud
article en

Abstract

Abstract Introduction. Adults with Ph-negative acute lymphoblastic leukemia (Ph- ALL) may not require allogeneic hematopoietic stem cell transplantation (alloHSCT) if they achieve negative measurable residual disease (MRD) after induction and consolidation therapy. However, it is unclear whether baseline genetic risk could more accurately identify patients (pts) who should receive chemotherapy (CHT) or alloHSCT. The aim of the PETHEMA LAL19 protocol (NCT04179929) was to evaluate the outcomes of pts assigned to differentiated post-induction therapy (CHT or alloHSCT) according to genetic features at diagnosis and MRD levels after induction. Methods. PETHEMA LAL19 was a multicenter study, including data from 94 centers across Spain. It enrolled newly diagnosed Ph-negative ALL pts, both T- and B-lineage, who received a pediatric-inspired treatment. Pts with high-risk (HR) genetics, those requiring two induction cycles to achieve complete remission (CR), and those with CR but MRD ≥0.01% after induction-1 (Ind-1) or MRD ≥0.001% after early consolidation and reinduction were allocated to alloHSCT. The remaining pts, considered standard-risk pts, were assigned to late consolidation and maintenance. HR genetics in B-ALL included: KMT2A rearrangement, hypodiploidy (<40 chromosomes) in pts aged >35 years, homozygous TP53 mutations/deletions, or co-occurrence of IKZF1 and CDKN2A deletions. HR genetics in T-ALL included absence of NOTCH1/FBXW7 mutations and/or mutations in K/NRAS or PTEN. Early T-cell precursor (ETP) ALL pts received a different treatment and all of them were assigned to receive an alloHSCT in first CR. All MRD and genetic studies were centralized. Results. Between end 2019 and August 2024, 436 eligible pts were enrolled (413 non-ETP and 23 ETP). In the non-ETP group, median age was 40 years (range, 18–60), 56% were male, median WBC count was 12×10⁹/L (0.4–740), and 80% had B-ALL. HR genetics were found in 36% (99/274) of B-ALL pts and 52% (34/65) of T-ALL cases. CR rate after Ind-1 was 84% (348/413) and increased to 95% (387/407) after Ind-1+Ind-2. MRD <0.01% was achieved in 63% (221/348) post-Ind-1 and in 91% (324/357) post-Ind-1+Ind-2. In the ETP-ALL group (n=23), median age was 29 years (range, 18-57), 57% were male, median WBC count was 29.2×10⁹/L (3.5-389), and five patients had CNS involvement. The CR rate was 74% (17/23) with 7 (41%) pts being MRD <0.01% after Ind-1 with FLAG-IDA. By intention-to-treat, 243 pts (61%) from the non-ETP group were allocated to alloHSCT and 157 (39%) to CT. The 3-year overall survival (OS) was 64% (95% CI, 58%–69%), and the cumulative incidence of relapse (CIR) was 39% (33%–45%). Among pts with CR and MRD <0.01% after Ind-1 and without HR genetics (n=109), 3-year OS was 81% (70%–89%). This compares favorably with 50% (34%–63%) observed in genetically HR pts (n=64) with similar MRD clearance, as well as with 58% for pts with CR and MRD ≥0.01% and 53% for pts who did not achieve CR after Ind-1 (p<0.001). A very-good risk group of patients (absence of HR genetics & CR after ind-1 with MRD<0.01% & MRD<0.001% after Re-Induction) showed a 3-year OS of 89% (78%–95%) and a 3-year CIR of 19% (10%-31%) with CHT only. In ETP-ALL pts, the 3-year OS was 61% (37%–79%), and the CIR was 25% (8%–48%). Conclusions. In adults with Ph- ALL, assigning post-remission treatment based on MRD and genetic risk is feasible. Genetic risk assessment among pts with good MRD clearance identified a subgroup with excellent prognosis without the need for alloHSCT. Thus, integrating genetic risk with MRD improves the precision of risk stratification.

BloodVol. 146(Supplement 1)
Universitat Autònoma de Barcelona (ES), Universidad de Salamanca (ES), Hospital Universitario de Canarias (ES), Hospital de Sant Pau (ES), Hospital General Universitario Gregorio Marañón (ES), Hospital Universitari i Politècnic La Fe (ES), Research Institute Hospital 12 de Octubre (ES), Hospital Son Llatzer (ES), Josep Carreras Leukaemia Research Institute (ES), Hospital Clínico Universitario de Valencia (ES), Hospital Universitario de Gran Canaria Doctor Negrín (ES), Marqués de Valdecilla University Hospital (ES), Hospital Universitario 12 De Octubre (ES), Ayuntamiento de Castellón de la Plana (ES), Hospital Universitario Puerta de Hierro Majadahonda (ES), Hospital Regional Universitario de Málaga (ES), Hospital San Pedro de Alcántara (ES), Hospital Clínic de Barcelona (ES), Hospital Universitario Reina Sofía (ES), Hospital General Universitari de Castelló (ES), Vall d'Hebron Hospital Universitari (ES), Hospital Juan Ramón Jiménez (ES), Hospital Universitario Fundación Jiménez Díaz (ES), Mútua Terrassa (ES), Hospital Del Mar (ES), Instituto de Biomedicina de Sevilla (ES), Hospital Universitario Central de Asturias (ES), Hospital de Cruces (ES), Hospital Universitario HM Sanchinarro (ES), Hospital General Universitario de Alicante Doctor Balmis (ES), Centro de Implantología Cirugía Oral y Maxilofacial (ES), Centro de Investigación del Cáncer (ES), Duran i Reynals Hospital (ES), Hospital Universitario Puerta del Mar (ES), Hospital General Universitario de Albacete (ES), Hospital Universitari Joan XXIII de Tarragona (ES), Hospital Universitario Virgen del Rocío (ES), Hospital Universitari Germans Trias i Pujol (ES), Hospital Jerez Puerta del Sur (ES), Hospital Universitari de Girona Doctor Josep Trueta (ES), Complejo Hospitalario Universitario de Albacete (ES), Hospital Clínico Universitario Virgen de la Victoria (ES), INCLIVA Health Research Institute (ES), Complejo Hospitalario de Pontevedra (ES)
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Acute Lymphoblastic Leukemia research
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